A Case of Relapsing Hyponatremia Associated with Fungal Sinusitis

Hyponatremia, which is defined as a serum sodium concentration ([Na⁺]) <135 mEq/L, is one of the most common electrolyte abnormalities in clinical practice. Even mild hyponatremia increases overall mortality risk and is an adverse prognostic factor across multiple commonly observed clinical conditions [1]. After detecting hyponatremia, it is necessary to classify the patient according to their volume status or the effective osmolality to treat appropriately. Hypotonic hyponatremia is an excess of water with existing sodium stores, which can be decreased, essentially normal, or increased [2]. Syndrome of inappropriate antidiuretic hormone (SIADH) is described as an inability to excrete a free water load, with inappropriately concentrated urine and low serum sodium levels caused by non-physiologic ADH secretion [3]. Although SIADH is a frequent cause of hyponatremia, there are many challenges in diagnosis and management because of diversities and heterogeneities in etiologies and variations in symptomatology. Delayed treatment due to diagnostic difficulties and management errors may result in prolonged hospitalizations associated with hyponatremia. Malignancies, infections, and drugs constitute most of the causes of SIADH [3, 4]. Although fluid restriction (FR), urea, and vasopressin receptor antagonists (vaptans) are included in the treatment of SIADH, treating the underlying cause is the cornerstone of therapy [3, 4]. The most common infections that cause hyponatremia are viral and bacterial infections [5]. The number of cases showing an association of fungal infection with hyponatremia is rare. We here present a 76-year-old man that shows relapsing hyponatremia due to Aspergillus flavus/oryzae sinusitis.

A 76-year-old man was admitted to the emergency department with complaints of altered consciousness and disorientation. The patient’s prior history was significant for hypertension, coronary artery disease that required coronary artery bypass grafting, benign prostatic hyperplasia, and operated vertex squamous cell carcinoma.

The patient’s sodium level was measured at 112 mEq/L. He had no history of nausea, vomiting, weight loss, convulsion, or diplopia. In his preadmission laboratory findings, his sodium level was within normal ranges (138 mEq/L). He was treated with hypertonic saline infusion. The possible cause of hyponatremia was thought to be his antihypertensive medication, hydrochlorothiazide, and the patient’s treatment was changed to telmisartan. After normalization of the sodium level to 135 mEq/L, the patient was discharged. Ten days after discharge, he was readmitted with the same complaints. The sodium level was measured at 126 mEq/L. He was hospitalized to find the underlying etiology of recurring hyponatremia.

The patient had a fever (38.4°C) at hospitalization; other vital signs were normal. Physical examination showed no signs of volume depletion or expansion. At laboratory findings, serum urea nitrogen was 15.24 mg/dL, serum creatinine was 0.63 mg/dL, serum uric acid was 3.0 mg/dL, fasting plasma glucose was 107 mg/dL, triglyceride was 116 mg/dL, the blood cortisol at 8 a.m. was 16.91 µg/dL, the plasma adrenocorticotropic hormone concentration was 13.0 pg/mL, the thyroid-stimulating hormone concentration was 0.852 μIU/mL, and all were in normal ranges. The C-reactive protein was evaluated as elevated (13.5 mg/dL). There were no findings at urinalysis, and neither acidosis nor alkalosis was detected on blood gas analysis.

Despite the limitation that we cannot evaluate serum and urine osmolarity in our hospital, the patient was assessed as SIADH after findings supporting euvolemia and his laboratory findings (serum sodium 126 mEq/L, accompanying spot urine sodium 116.7 mEq/L) and exclusion of possible causes. He was then evaluated for the underlying etiology.

There were no findings in abdominal and pelvic imaging. In thoracic computed tomography, bilateral distal paratracheal lymph nodes with a shorter diameter of less than 10 mm were detected. No parenchymal mass was observed. Sarcoidosis was excluded from the patient’s clinical and laboratory findings (such as hypercalcemia, hypercalciuria, and elevated serum ACE level).

Due to the feverish condition, increased C-reactive protein level, and intermittent confusion, the laboratory tests were examined to exclude possible infections. Blood cultures and urine cultures were sterile. A lumbar puncture was performed, and bacterial and viral meningitis were excluded with serological tests and polymerase chain reaction (Table 1).

The patient had pituitary and cranial magnetic resonance imaging (MRI) to rule out possible pathologies that may cause hyponatremia. MRI showed findings favoring acute sinusitis in the right sphenoid sinus, plus leptomeningeal contrast enhancement compatible with meningeal involvement due to sphenoidal sinusitis.

The patient underwent endoscopic sinus surgery. Direct microscopy from biopsy specimens in the examination with potassium hydroxide and calcofluor white revealed septate hyphae. In the postoperative period, treatment was started with voriconazole 6 mg/kg loading every 12 h and 4 mg/kg as a maintenance dose. The growth of A. flavus/oryzae (MALDI-TOF MS score 2.48, Bruker Daltonics, Germany) was detected in culture. Antifungal susceptibility testing was performed according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines, and the minimal inhibitory concentration (MIC) value of voriconazole was 2 mg/L [6].

The patient was followed up with FR and oral sodium chloride administration for hyponatremia. As he did not respond to these measures, tolvaptan was started at 7.5 mg/day. Despite alleviating neurological symptoms with antifungal treatment and tolvaptan, the normalization of serum sodium level was observed on 7th day of voriconazole and 21st day of tolvaptan. After a 3-week IV voriconazole therapy, the serum sodium value was measured at 139 mEq/L, and he was discharged with oral voriconazole 250 mg BID, which was continued for 6 months. Follow-up MRI scans proved regression of contrast-enhancing lesions. At the end of the follow-up, serum sodium values were consistently in the range of 134–137 mEq/L, demonstrating the successful outcomes of the treatment.

Hyponatremia is one of the most common electrolyte imbalances that present varying clinical manifestations. Hyponatremia is associated with prolonged hospital stays, a higher risk of readmission, and increased morbidity and mortality [1, 6]. After classifying the patients according to effective plasma volume and tonicity, further evaluation for possible etiologies is essential. Although it seems simple to diagnose in the light of theoretical classifications, there may be difficulties and delays in administering targeted therapy due to faint clinical findings and various causes that may lead to hyponatremia.

Treatment for the main SIADH etiology has a most significant role. The European Clinical Practice Guideline recommends FR as a first-line therapy, except for etiology-based therapy [3]. Second-line therapy options are increased solute intake with urea or a combination of low-dose loop diuretics with sodium chloride [3, 4]. Limited patient compliance with FR and oral sodium chloride are causes of inadequate treatment responses [3, 4]. Except for the mentioned therapies, demeclocycline, lithium, urea, and vaptans have been used for therapy [3]. Due to possible harmful adverse effects, demeclocycline and lithium are not recommended for any degree of hyponatremia [3]. Despite the positive results of urea therapy on SIADH [3, 4], the lack of availability of preparations in our country is a limitation of management.

Tolvaptan is an oral, selective, non-peptide V2 receptor antagonist [7]. Despite its success in correcting sodium levels, tolvaptan must be used carefully due to possible rapid overcorrection and hepatotoxicity risk, and there is insufficient data in asymptomatic severe hyponatremia patients [3, 4].

Bacterial and viral infections are the major infectious reasons associated with hyponatremia [5]. Although patients with fungal rhinosinusitis have been described in the literature [8‒10], only 1 case report showed its co-occurrence with hyponatremia [10]. Our case is the first in the literature to report the multidisciplinary management of both hyponatremia and fungal sinusitis. Moreover, our case has shown the importance of detailed investigations to find the underlying cause and reach a definite treatment for hyponatremia.

Although fungal rhinosinusitis and meningitis are primarily seen in immunocompromised patients, it has been shown that they can also be seen in immunocompetent individuals [8, 10, 11]. Aspergillus is the fungus most involved in paranasal sinuses [12]. Aspergillus fumigatus and A. flavus are the most common species affecting paranasal sinuses [10‒12]. When we compare the pathogenicity of A. fumigatus and A. flavus, A. flavus spores are larger. Thus, they are mainly trapped in the upper respiratory tract, which is associated with upper respiratory tract infections [13]. Our patient is a retired civil engineer with a history of occupational Aspergillus exposure, which may contribute to the slowly progressing fungal sinusitis. The final diagnosis of the patient is “chronic invasive fungal sinusitis.” Surgical debridement and adjunct mold-active antimicrobial treatment are warranted for a favorable outcome [14]. Voriconazole is the drug of choice for aspergillosis. Voriconazole may diffuse to cerebrospinal tissues efficiently, making it a promising oral option for treating fungal sinusitis with dural involvement [14]. While no clinical breakpoint was determined for voriconazole against A. flavus, EUCAST reports the epidemiological cutoff value as 2 mg/L [15]. Based on the voriconazole MICs generated for 55 A. flavus complex strains isolated in our center, only one isolate was found to be non-wild-type (MIC = 4 mg/L). These data and the voriconazole MIC (2 mg/L) for the strain isolated from the tissue sample of this patient suggest that secondary resistance-related mutations are expected to be rare for voriconazole against A. flavus. These in vitro data herewith support the use of voriconazole in the treatment of A. flavus infections.

In conclusion, hyponatremia is the most common electrolyte disturbance. In this case report, we described a 76-year-old man with relapse of A. flavus/oryzae sinusitis and SIADH. It is essential to initiate appropriate treatment as soon as possible to prevent short- and long-term complications associated with hyponatremia. This report is significant as it is the first case in which the coexistence of A. flavus complex sinusitis and hyponatremia has been demonstrated in the literature. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000541579).

We would like to thank all our colleagues who helped us in the management of the case.

Written informed consent was obtained from the patient for publication of the details of his medical case and any accompanying images. Ethical approval is not required for this study in accordance with local guidelines.

The authors declare that they have no conflicts of interest.

This article did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Dr. Arici and Dr. Apaydin Rollas, who were involved in the care of this patient, conceived the original idea for the case report and revised the manuscript before publication. Dr. Ozberk and Dr. Onal collected the patient information. Dr. Gulmez and Dr. Arikan-Akdagli conducted fungal culture and antimicrobial susceptibility testings. Dr. Inkaya and Dr. Unal managed antifungal therapy in light of culture results and clinical response. All authors read and approved the final manuscript.

The data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon reasonable request.